tbuckley/cabot-search huggingface dataset:
Abstract 14959: Mitochondrial Transplantation in Pediatric and Neonatal Porcine Hearts in a Model of DCD Heart Transplantation
Authors: Victor Sanchez Alemany, Rio Nomoto, Mossab Saeed, Aybuke Celik, William Regan, Greg Matte, Sitaram Emani, Pedro J Del Nido, James D MCCULLY
Journal: Circulation (2022)

Introduction: Heart transplantation in pediatric and neonatal patients is limited by the donor pool. Donation after circulatory death (DCD) could potentially expand the donor pool by offering an additional source of cardiac allografts. In this study, we investigated the efficacy of mitochondrial transplantation to enhance myocardial function in pediatric and neonatal DCD hearts. Hypothesis: Autologous mitochondrial transplantation enhances the viability and function of pediatric and neonatal DCD donor hearts. Methods: Circulatory death was induced by extubation in neonatal (25 - 50g heart weight, representing 4-16 month human) and pediatric (68 - 98g heart weight, representing 4-6 year human) swine model. Hearts were subjected to 20 min of warm ischemia and 10 min of cold cardioplegic arrest and then harvested. The aorta and pulmonary artery were cannulated, inferior and superior venae cavae ligated and a balloon was inserted in the left ventricle. The hearts were then mounted on the ex situ perfusion device. After 15 minutes of reperfusion, hearts received either vehicle alone ([VEH], 10 mL n = 6) or vehicle containing autologous mitochondria ([MT] 5x10 9 in 10 mL; n = 6). A Sham non-ischemic group (n = 4) did not undergo warm ischemia, mimicking donor after brain death (DBD). Hearts were machine perfused for 2 hours unloaded and 2 hours of loaded conditions. Results: Following 4 hours of reperfusion, neonatal and pediatric DCD hearts receiving VEH showed significantly decreased myocardial function and viability as compared to Sham non-ischemic control hearts. In contrast, in both neonatal and pediatric DCD hearts receiving MT, LVDP, dP/dt max, and fractional shortening were significantly increased (p &lt; 0.001 for each) and were equal or better than that observed in Sham non-ischemic hearts. Infarct size was significantly decreased in both neonatal and pediatric DCD hearts receiving MT as compared to VEH (p &lt; 0.001). Conclusions: Mitochondrial transplantation provides for significantly enhanced preservation of myocardial function and viability in neonatal and pediatric DCD hearts that is equivalent to or better than that observed in DBD hearts. Mitochondrial transplantation provides a possible option to expand the pediatric and neonatal heart donor pool.
Abstract 15068: Regional Variation in Atrial Fibrillation Ablation Care for Medicare Beneficiaries Across the United States
Authors: Jonathan Hanna, James V Freeman, James Hummel, Jeptha P Curtis, Zhenqiu Lin, Joseph Akar, Rohan Khera
Journal: Circulation (2022)

Background: Despite recognition of the role of early ablation for favorable long-term outcomes in atrial fibrillation (AF), access to these services requires substantial resources and expertise. We investigated county-level variation in the availability of AF ablation care for the Medicare population. Methods: In Medicare physician claims from 2019 linked to AHRQ county characteristics, we evaluated the volume of AF ablation per 100,000 population over the age of 65 years across US counties. We examined county characteristics associated with local access to ablation care, evaluating county-level differences in population composition, cardiovascular risk factor burden, and access to primary care (number per 100,000 population). Results: A total of 64,055 beneficiaries received AF ablation care from 1,501 physicians across the US. Of 3,143 U.S. counties, 403 (12.8%) in 2019 had any ablation procedures. In counties with local ablation care, a median 182 beneficiaries per 100,000 persons ≥65 years of age underwent AF ablation, with a wide variation in volumes across counties - interquartile range 97 per 100,000 to 337 per 100,000 ( Figure). Of the total estimated 49,238,690 persons ≥65 years of age across counties within the United States and District of Columbia, 18,639,381 (37.9%) resided in counties without AF ablation services in the same county. In adjusted analyses, counties without local AF ablation services did not differ in demographic characteristics or prevalence of cardiovascular risk factors but were characterized by lower access to primary care physicians and lower educational attainment among county residents (P&lt;0.01 for both). Conclusions: Only 1 in 8 US counties has local AF ablation care, with over one-third of U.S. adults ≥65 years of age residing in counties without local services. Patient-centered care necessitates greater accessibility for many patients without proximity to AF ablation care, especially with expanding indications.
Abstract 15009: Detection of a Low Ventricular Stiffness With Preserved Ejection Fraction Phenotype in Single Ventricle Physiology
Authors: Shahryar M Chowdhury, Eric M Graham, Donald R Menick, Andrew M Atz
Journal: Circulation (2022)

Introduction: Patients with single ventricle physiology frequently demonstrate decreased exercise tolerance after the Fontan operation. The objective of this study was to investigate the contribution of ventricular stiffness to exercise function in these patients. Hypothesis: We hypothesized that ventricular stiffness, both extremes of high and low stiffness, would be associated with exercise tolerance in Fontan patients. Methods: We previously validated an echocardiographic measure of ventricular stiffness, lateral Doppler E: tissue Doppler e’/end-diastolic volume (lateral E:e’/EDV) in children. Core-lab echocardiograms and exercise test results were obtained from the publicly-available Pediatric Heart Network Fontan Cross-sectional Study database. Exercise function was quantified as % predicted VO 2 . Ejection fraction (EF) was considered abnormal if &lt; 50%. Diastolic function was defined as high stiffness if the lateral E:e’/EDV was &gt; 90th percentile or low stiffness if &lt; 10th percentile. Patients were divided into four groups: 1 = normal EF and normal diastolic function, 2 = decreased EF with normal diastolic function, 3 = normal EF with high ventricular stiffness, and 4 = normal EF with low ventricular stiffness. Results: 239 patients (61% left, 29% right, 10% mixed ventricular dominance) had EF, lateral E:e’/EDV, and VO 2 measured. Differences between groups are reported in the Table. Conclusion: Single ventricle patients with both high and low stiffness and preserved EF had worse exercise capacity than patients with both normal and abnormal EF. To our knowledge, this is the first study detecting a low stiffness heart failure phenotype in single ventricle physiology. Future studies should further investigate the pathophysiologic mechanisms that lead to these extremes of stiffness in Fontan patients.
Abstract 15031: Anticoagulation Status and Risk of Stroke Following Leak-Closure Procedure for Residual Leak After Occlusion of the Left Atrial Appendage in Patients With Atrial Fibrillation
Authors: Sanghamitra Mohanty, Domenico G Della Rocca, Karim Baho, Sai Shishir Shetty, ANGEL QUINTERO MAYEDO, Bryan MacDonald, Carola Gianni, Issa Asfour, Danielle Kessler, Mohamed Bassiouny, G Gallinghouse, John Burkhardt, Rodney Horton, Amin Al-Ahmad, Luigi Di Biase, Andrea Natale
Journal: Circulation (2022)

Introduction: Studies have shown a correlation between leaks following left atrial appendage occlusion procedure and thromboembolic (TE) events. Hypothesis: We investigated the benefits of leak-closure in terms of safe discontinuation of oral anticoagulation (OAC) and minimization of the stroke-risk. Methods: Consecutive patients undergoing leak-closure procedure at our institution were included in the analysis. Procedures included closure with endovascular coils or Amplatzer plug or by using radiofrequency ablation (RFA). Persistence of the leak was verified by multiplane transesophageal echocardiogram (TEE) using color Doppler. Follow-up TEE were performed 60 ± 15 days post-procedure to evaluate LAA closure and patients were kept on OAC until then. After confirmation of closure, they were transitioned to ASA 81 mg/day. All patients were monitored quarterly for thromboembolic (TE) events. Results: A total of 139 post-Watchman patients undergoing leak-closure were included in the analysis (RFA: 10, Amplatzer plug: 5, coil-closure: 124). Pre-coil closure TE events were reported in 7 (5%) subjects. Moderate (3-4 mm) and severe (≥5 mm) leak were detected in 118 (85%) and 21 (15%) patients respectively. After the leak-closure procedure, complete sealing of the leak was confirmed at the follow-up TEE in 138 (99.2%) patients. Figure 1 shows significant reduction in TE events following the leak-closure procedure (p=0.031). During the 2-year follow-up period, six deaths were reported due to unrelated causes. Of the remaining 133 subjects, two patients were on DAPT because of history of coronary artery disease, two with prior stroke were on half-dose OAC and the remaining 129 (95.8%) were on ASA 81 mg/day. No TE events were reported in patients that transitioned to ASA. Conclusions: In this series, successful percutaneous leak-closure not only minimized the risk of stroke but also enabled the majority of patients to discontinue OAC without any TE events.
Abstract 14923: A Special Type Aortic Left Ventricular Tunnel With Bicuspid Aortic Valve: A Case Report
Authors: Yi Song, Jindou An, Huiruo Liu
Journal: Circulation (2022)

Introduction: Aortic-left ventricular tunnel (ALVT) is an extremely rare congenital cardiac lesion that is an abnormal passage connecting the ascending aorta to the left ventricle. ALVT can be diagnosed by the use of real-time two-dimensional and continuous-wave Doppler echocardiography. Case presentation: A two-year and seven-month-old boy with recently diagnosed influenza presented to the hospital because of severe tachypnea and fatigue after running. Physical examination revealed a grade 3/6 systolic and diastolic murmur at the second and third left intercostal space. Transthoracic echocardiography (GE E95 with a 5-MHz scanning head) demonstrated that the aortic valve was a bicuspid aortic valve (BAV) with mild-moderate insufficiency during diastole, the peak systolic velocity (PSV) and gradient of aortic valve were 1.9m/s and 14mmHg, respectively; The aortic sinotubular junction (ASJ) was stenotic, the PSV and gradient of ASJ were 2.7m/s and 29mmHg, respectively; A tubular-like structure originated in the outlet septum beneath the right coronary cusp and terminated in the ascending aorta superior to the right coronary aortic sinus (Fig. A, B), CDFI and continuous-wave Doppler showed unobstructed to-and-fro (systolic and diastolic) flow in the tunnel with a high-velocity color signal that aliased during systole (Fig. C-E). Clinical considerations for congenital heart disease: ALVT combines BAV with aortic insufficiency and supravalvar aortic stenosis. The patient was referred for possible surgical correction. Discussion: In this patient, the type of ALVT does not belong to any one of Hovaguimian’s classifications. Two-dimensional echocardiography can display the tunnel-like structure of ALVT in real-time, and CDFI can identify that two-stage bidirectional shunted blood flow, systolic ventricular ejection occurs through both the tunnel and the semilunar valve, and the diastolic flow reverses from the aorta to ventricle via ALVT.
Abstract 14994: One-Year Mortality and Reoperation Among Patients With Infective Endocarditis After Transcatheter or Surgical Aortic Valve Replacement
Authors: Mark Jacobs, Alan Abboud, Brandon Muncan, Aikaterini Papamanoli, Puja B Parikh, Hal Skopicki, Andreas P Kalogeropoulos
Journal: Circulation (2022)

Background: With improving technology and experience, indications for transcatheter aortic valve implantation (TAVI) have expanded to include younger patients and those at moderate surgical risk, leading to increasing use of TAVI as an alternative to surgical aortic valve replacement (SAVR). As a result, post-TAVI infective endocarditis (IE) is increasingly common. Data on post-TAVI IE in comparison to post-SAVR IE outcomes are limited. Methods: Using data from the TriNetX Research Network, we identified (1) a cohort of patients who underwent TAVI between 1/1/2016 and 12/31/2020 (CPT procedure code 1021150) and developed IE (captured with ICD-10 codes I33, I38, or I39) after the procedure; and (2) a propensity score-matched cohort of patients who underwent SAVR (CPT procedure codes 1006141, excluding any associated transcatheter procedures) and developed IE. Both cohorts were required to have at least 1 week follow-up, i.e., deaths within 7 days of IE were excluded. We matched the cohorts for demographics and clinically relevant background characteristics. Results: We identified 713 patients with post-TAVI IE and 713 matched patients with post-SAVR IE. The baseline characteristics were well balanced, as indicated by standardized mean differences &lt;0.1, Table 1. The Kaplan-Meier 1-year mortality between 7 days and 1 year (as deaths before 7 days were excluded) was 18.4% in the TAVI cohort (131 events) vs. 11.4% in the SAVR cohort (81 events), HR 1.62 (95%CI 1.23-2.14; P=0.001). Aortic valve reoperation was uncommon in both groups, with 13 and 10 events in the TAVI and SAVR groups, respectively (1.8% vs. 1.4%; HR 1.43, 95%CI 0.61-3.34; P=0.41). Conclusions: In this comparative, propensity-matched cohort study, 1-year mortality after an episode of IE was higher among TAVI recipients vs. their SAVR counterparts. Repeat aortic valve procedures were uncommon in both groups. Prospective studies are needed to elucidate the causes of excess mortality among TAVI recipients.
Abstract 14941: Association of WATCH-DM Risk Score With Cardiac Abnormalities and Prevalence of Diabetic Cardiomyopathy: A Prospective Cohort Study
Authors: Zainali Chunawala, Viraj Raygor, Matthew Segar, Alvin Chandra, Ambarish Pandey
Journal: Circulation (2022)

Introduction: Diabetic cardiomyopathy (DbCM) is characterized by abnormal cardiac structure or function in the absence of cardiovascular disease (CVD). We assessed whether WATCH-DM, a validated risk score to predict incident heart failure (HF) in patients with DM, can identify DbCM. Methods: We prospectively enrolled 150 individuals with DM free of known CVD or overt HF in a single-center institution. The presence of DbCM was calculated using different definitions: 1) least restrictive: ≥1 echocardiographic abnormality (left atrial enlargement, left ventricular hypertrophy, diastolic dysfunction); 2) intermediate restrictive: ≥2 echocardiographic abnormalities; and 3) most restrictive: elevated N-terminal pro-B-type natriuretic peptide levels (&gt;125 in normal/overweight or &gt;100 pg/mL in obese) plus ≥2 echocardiographic abnormalities. DbCM prevalence was compared across high (scores ≥ 11) and low (scores &lt; 11) WATCH-DM using chi-squared test. Adjusted logistic regression models were used to evaluate the association between WATCH-DM and components of DbCM. Results: The prevalence of DbCM ranged from 60.7% to 7.3% in the least and most restrictive definitions, respectively. Subjects with high (vs. low) WATCH-DM score were more often males (58% vs 32%), older (71 vs 68 years) and had a longer duration of DM (13 vs 10 years). Moreover, the concentration of NT pro-BNP was observed to be significantly higher in the high WATCH-DM cohort. Across definitions, individuals with high WATCH-DM had a numerically higher prevalence of DbCM ( Fig. A ). Among individual components, high WATCH-DM was associated with a higher risk of diastolic dysfunction (OR [95% CI] = 2.53 [1.20-5.54]) ( Fig. B ). We observed no significant differences in LV hypertrophy or LA enlargement across WATCH-DM scores. Conclusion: High WATCH-DM risk score is associated with a higher prevalence of DbCM and echocardiographic abnormalities and may be an effective tool for identifying patients with DbCM.
Abstract 14950: Single-Cell Transcriptomic Analysis Reveals Emergence of Inflammatory and Activated Arterial Endothelial Cells Promoted by Cross-Talk With Mural Cells During Development of Severe Pulmonary Arterial Hypertension
Authors: Nicholas D Cober, Emma McCourt, Rafael Soares Godoy, Yupu Deng, Ken Schlosser, David Cook, Liyuan Wang, Duncan J Stewart
Journal: Circulation (2022)

Introduction: Pulmonary arterial hypertension (PAH) is a lethal disease characterized by occlusive arterial remodelling thought to be triggered by endothelial cell (EC) injury; however, the pathobiological mechanisms are poorly understood. We employed single cell RNA sequencing (scRNAseq) to define transcriptomic changes in the SU5416/chronic hypoxia (SU/CH) rat model. Methods: Sprague-Dawley rats were injected with 20mg/kg SU subcutaneously and exposed to 3 weeks of CH (10% O 2 ). Right ventricular systolic pressure (RVSP) was measured at baseline, 1, 3, 5, and 8-weeks, then lungs were explanted, digested, and dissociated into single cells which were sequenced using the 10x genomics platform. Results: Elevation of RVSP plateaued at &gt;100 mmHg by 5 weeks. Dimensionality reduction of the scRNAseq data was performed using Uniform Manifold Approximation and Projection (UMAP) analysis resulting in 24 lung clusters. Cell prioritization analysis performed using Augur identified vascular cells as the most affected by SU/CH, including arterial ECs, pericytes, and gCap ECs. After sub-clustering the EC populations, eight distinct clusters were identified representing all expected subtypes (capillary, arterial, venous, and lymphatic). As well, two novel EC clusters were detected. The first showed reduced expression of classical EC genes ( Cdh5 , Cldn5 ) and increased proinflammatory markers ( RT1-Da , Cd74 ), termed ‘inflammatory’ ECs. The second was an arterial cluster that exhibited reduced expression of Dll4 and increased Cxcl12 and Fn1 , termed ‘activated’ arterial ECs. Both populations emerging at 1-week post SU, persisting throughout PAH progression. While many EC populations showed marked differential gene expression (DGE) at 1 week, the activated arterial cluster was the only cluster showing progression of DGE throughout progression of PAH. Receptor-ligand analysis with NicheNet identified activated arterial ECs as a top receiver cell responding to multiple ligands, including Bmp4/5 , Col4a1 , and Vegfa/c, which were largely derived from mural fibroblasts. Conclusion: Emergence of inflammatory and activated arterial ECs likely contribute to vascular remodelling associated with PAH promoted by cross-talk with lung stromal cells.
Abstract 14952: Lysosomal Regulation of Calcium and Iron Homeostasis and Ferroptosis in Mouse Cardiomyocytes
Authors: Sri Harika H Pamarthi, Nadezhda Fefelova, Judith K Gwathmey, Junichi Sadoshima, Lai-Hua Xie
Journal: Circulation (2022)

Background: Lysosomes are specific organelles that contain various digestive enzymes and also store both iron (Fe) and calcium (Ca). However, it is not known whether cytosolic and mitochondrial Fe and Ca handling and ferroptosis are modulated by lysosomal dysfunction. We aimed to evaluate the interaction between lysosomal, mitochondrial and cytosolic Ca and Fe dynamics and its relevance to cardiomyocyte function and ferroptosis. Methods: Left ventricular myocytes were enzymatically isolated from mouse hearts. Cytosolic Ca i was imaged using fluo-4-AM. Cytosolic Fe was determined with Phen green while mitochondrial Fe was measured using rhodamine B-[(1,10-phenanthroline-5-yl)-aminocarbonyl]benzyl ester (RPA). Mitochondrial membrane potential (Δ Ψ m ) was monitored by TMRM. Ferroptosis was analyzed using the Live/Dead cell viability assay. Results: Treatment with nicotinic acid dinucleotide phosphate (NAADP-AM 50 nM), an agonist of the two pore channel in the lysosomal membrane, increased the aptitude of the Ca i transient (1.94 ± 0.09 to 2.41 ± 0.14, n = 12, p &lt; 0.05) and induced spontaneous Ca i waves. Diastolic Ca i became elevated (1.00 to 1.30 ± 0.10, n = 12, p &lt; 0.05) in intact myocytes. Elevation of basal Ca i level and an increase in spontaneous Ca i wave amplitude and frequency were confirmed in saponin-permeabilized myocytes. NAADP also increased the level of cytosolic Fe. These results suggest both Ca and Fe are released from lysosomes into the cytosol by NAADP. Our previous studies have shown that mitochondrial Fe uptake is essential for Fe overload-induced ferroptosis in cardiac myocytes. Therefore, we further assessed how lysosome function affects mitochondrial Fe loading and induction of ferroptosis. We found that NAAPD treatment resulted in an elevation of mitochondrial Fe levels (by 28.4 ± 3.5 %, n=23, p &lt;0.05), depolarization of Δ Ψ m as well as resulted in an increased sensitivity to Fe overload-induced ferroptosis. Similar results were observed using GPN that causes selective disruption of lysosomes. Conclusions: Lysosomal dysfunction may contribute to mishandling of Ca and Fe in myocytes and promote the occurrence of ferroptosis. A lysosomal storage disorder mouse model ( i.e. RagA/B KO) will be assessed in future studies.
Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5’-untranslated region of UNC45A
Authors: Runar Almaas, Monica Atneosen-Åsegg, Mari Eknes Ytre-Arne, Maria Melheim, Hanne Sørmo Sorte, Dana Cízková, Henrik Mikael Reims, Aleš Bezrouk, Sean Philip Harrison, Janne Strand, Johanne Uthus Hermansen, Sofie Strøm Andersen, Kristin Louise Eiklid, Jaroslav Mokrý, Gareth John Sullivan, Asbjørg Stray-Pedersen
Journal: Journal of Hepatology (2023)

Lymphedema cholestasis syndrome 1 or Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. The genetic background of this autosomal recessive disease was unknown up to now.A total of 26 patients with Aagenaes syndrome and 17 parents were investigated with whole-genome sequencing and/or Sanger sequencing. PCR and western blot analyses were used to assess levels of mRNA and protein, respectively. CRISPR/Cas9 was used to generate the variant in HEK293T cells. Light microscopy, transmission electron microscopy and immunohistochemistry for biliary transport proteins were performed in liver biopsies.One specific variant (c.-98G>T) in the 5'-untranslated region of Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome. Nineteen were homozygous for the c.-98G>T variant and seven were compound heterozygous for the variant in the 5'-untranslated region and an exonic loss-of-function variant in UNC45A. Patients with Aagenaes syndrome exhibited lower expression of UNC45A mRNA and protein than controls, and this was reproduced in a CRISPR/Cas9-created cell model. Liver biopsies from the neonatal period demonstrated cholestasis, paucity of bile ducts and pronounced formation of multinucleated giant cells. Immunohistochemistry revealed mislocalization of the hepatobiliary transport proteins BSEP (bile salt export pump) and MRP2 (multidrug resistance-associated protein 2).c.-98G>T in the 5'-untranslated region of UNC45A is the causative genetic variant in Aagenaes syndrome.The genetic background of Aagenaes syndrome, a disease presenting with cholestasis and lymphedema in childhood, was unknown until now. A variant in the 5'-untranslated region of the Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome, providing evidence of the genetic background of the disease. Identification of the genetic background provides a tool for diagnosis of patients with Aagenaes syndrome before lymphedema is evident.